This invention relates to compositions and methods for achieving a therapeutic effect such as lowering blood pressure and treating congestive heart failure in a mammal. More specifically, this invention relates to synergistic compositions comprising amounts of at least two therapeutic agents selected from the group consisting of a renin-inhibitor, an angiotensin I converting enzyme inhibitor and an angiotensin II antagonist, which inhibitors and antagonists are present in amounts sufficient to cause synergistic therapeutic effects such as lowering blood pressure and treating congestive heart failure in a mammal. Further, this invention relates to methods for achieving synergistic therapeutic effects such as lowering blood pressure and treating congestive heart failure in a mammal which methods comprise administering to said mammal, either sequentially in any order or simultaneously, amounts of at least two therapeutic agents selected from the group consisting of a renin inhibitor, an angiotensin I converting enzyme inhibitor and an angiotensin II antagonist, in amounts sufficient to achieve a synergistic therapeutic effect.
Examples of renin inhibitors which inhibit the angiotensinogen cleaving action of the enzyme renin are described in U.S. Pat. No. 4,814,342 and U.S. Pat. No. 4,895,834. The teachings thereof are incorporated herein by reference. Such renin inhibitors, among others, are useful in lowering blood pressure in a mammal and in treating congestive heart failure as well as for achieving other therapeutic effects.
Examples of inhibitors of angiotensin I converting enzymes are described in U.S. Pat. Nos. 4,046,889 and 4,374,829. The teachings thereof are incorporated herein by reference. Among the known angiotensin I converting enzyme inhibitors are captopril, enalapril, lisinopril and ramipril. Such angiotensin I converting enzyme (ACE) inhibitors, among others, are useful in lowering blood pressure in a mammal and in treating congestive heart failure as well as for achieving other therapeutic effects.
Examples of angiotensin II antagonists (AII antagonists) are described in U.S. Pat. No. 4,355,040, U.S. Pat. No. 4,880,804, EP 253310, EP 323841 and EP 324377. The teachings thereof are incorporated herein by reference. Included among the known AII antagonists is Dup753. Such AII antagonists, among others, are useful in lowering blood pressure in a mammal and in treating congestive heart failure.
A study has been reported comparing the effects of a renin inhibitor known as H77 with the effects of an ACE inhibitor, captopril. Tree, M., et al., J. Hypertension 7: 351-355 (1989). That study suggests, inter alia, that, due to the similar effects achieved, the renin inhibitor and ACE inhibitor act by the same mechanism of reducing angiotensin II. Another study has been reported comparing the hemodynamic effects of MK-422, an ACE inhibitor, and a renin inhibitor and concludes that the responses under study to each were identical. Sweet, C. S., et al., J. Cardiovasc. Pharmacol. 6: 1067-1075 (1984). Yet another study comparing the effect of the renin inhibitor H77 with the ACE inhibitor captopril is reported in Oldham, A. A., et al., J. Cardiovasc. Pharmacol. 6: 672-677 (1984). In that study it is reported that injection of captopril during H77 infusion had a small additional hypotensive effect.
Until the invention described herein, there was no report of use of a renin inhibitor together with an ACE inhibitor to achieve a synergistic blood pressure lowering effect or any other synergistic therapeutic effects such as a congestive heart failure treating effect by employing amounts of a renin inhibitor and an ACE inhibitor.
Further, until this invention, there was no report of use or intent to use a renin inhibitor together with an AII antagonist, an ACE inhibitor together with an AII antagonist or a renin inhibitor together with an ACE inhibitor and an AII antagonist to achieve synergistic therapeutic effects such as a synergistic blood pressure lowering effect or a synergistic congestive heart failure treating effect.